EP0175551B1 - Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds - Google Patents

Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds Download PDF

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Publication number
EP0175551B1
EP0175551B1 EP85306479A EP85306479A EP0175551B1 EP 0175551 B1 EP0175551 B1 EP 0175551B1 EP 85306479 A EP85306479 A EP 85306479A EP 85306479 A EP85306479 A EP 85306479A EP 0175551 B1 EP0175551 B1 EP 0175551B1
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EP
European Patent Office
Prior art keywords
formula
oxindole
chloro
hydrogen
carbons
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Expired
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EP85306479A
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German (de)
English (en)
French (fr)
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EP0175551A1 (en
Inventor
Saul Bernard Kadin
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Pfizer Corp SRL
Pfizer Inc
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Pfizer Corp SRL
Pfizer Inc
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Priority to AT85306479T priority Critical patent/ATE42950T1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to new chemical compounds. More particularly, these new chemical compounds are derivatives of 2-oxindole and they are further substituted at the 1- and the 3-position by an acyl group. These new chemical compounds are inhibitors of both the cyclooxygenase (CO) and the lipoxygenase (LO) enzymes.
  • CO cyclooxygenase
  • LO lipoxygenase
  • the compounds of this invention possess analgesic activity in mammals, particularly man, and they are useful therefore for acute administration for ameliorating or eliminating pain, such as the pain experienced by patients recovering from surgery or trauma.
  • the compounds of this invention are useful for chronic administration to mammals, particularly man, to alleviate the symptoms of chronic diseases, such as the inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
  • US-A-3767653 describes anti-inflammatory agents which may be 3-acyl-2-oxindole compounds having an alkyl group substituted with a basic nitrogen-containing group at the 1 position.
  • US-A-3634453 describes 2-oxo-2, 3-dihydroindoles-3-carboxamides having chemotherapeutic properties.
  • US-A-3351630 describes a-hydroxy, alkoxy and acyloxy 3-indolyl acetic acid compounds having an aroyl radical attached to the nitrogen of the indole ring. These compounds are said to have anti- inflammatory activity.
  • This invention provides novel 1,3-diacyl-2-oxindole compounds of the formula and the pharmaceutically-acceptable base salts thereof, wherein
  • X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo and trifluoromethyl;
  • R' is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7 carbons, phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, naphthyl and ⁇ (CH 2 ) n ⁇ Q ⁇ R°;
  • n is zero, 1 or 2;
  • Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine and pyrazine; and R° is hydrogen or alkyl having 1 to 3 carbons;
  • R 2 is alkyl having from 1 to 5 carbons.
  • Said compounds of formula I are active as analgesic agents, and as agents for treating inflammatory diseases, such as the arthritides. Accordingly, this invention also provides a method of eliciting an analgesic response in a mammalian subject, especially man; a method of treating an inflammatory disease in a mammalian subject, especially man; and pharmaceutical compositions comprising a compound of formula I and a pharmaceutically-acceptable carrier.
  • a preferred group of compounds of this invention consists of the compounds of formula I, wherein X and Y are each hydrogen and R' is selected from the group consisting of 2-furyl, 2-thienyl, 3-pyridyl and (2-thienyl)methyl.
  • a further preferred group of compounds of this invention consists of the compounds of formula I, wherein X is 5-chloro, Y is hydrogen and R' is selected from the group consisting of 2-furyl, 2-thienyl, 3-pyridyl and (2-thienyl)methyl.
  • Especially preferred individual compounds of the invention are:
  • a preferred sub-group of compounds of the formula II consists of those compounds in which X is hydrogen, 5-fluoro, 5-chloro or 5-trifluoromethyl; Y is hydrogen, 6-fluoro, 6-chloro or 6-trifluoromethyl; and R 2 is alkyl having 1 to 5 carbons; provided that X and Y are not both hydrogen.
  • the compounds of formula II in said latter preferred sub-group are novel, and as such they form part of this invention.
  • This invention relates to the compounds of formula I, and those compounds are named as derivatives of 2-oxindole, the compound of the structure;
  • analgesic and anti-inflammatory compounds of this invention of formula I wherein X, Y, R I and R 2 are defined previously, are capable of enolization, and therefore they can exist in one or more tautomeric (enolic) forms. All such tautomeric (enolic) forms of the compounds of formula I are considered to be within the scope of this invention.
  • An inert solvent is one which will dissolve at least one of the reactants, and will not adversely interact with either of the reactants or the product.
  • a polar, aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, is commonly used.
  • N-hydroxyimide esters such as N-hydroxysuccinimide and N-hydroxyphthalimide esters
  • 4-nitrophenyl esters such as thiol phenyl esters
  • thiol esters such as thiol phenyl esters
  • 2,4,5-trichlorophenyl esters and the like.
  • preferred basic agents are tertiary amines, such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4-(N,N-dimethylamino)pyridine.
  • a lower-alkanol solvent e.g. ethanol
  • an alkali metal salt of the lower-alkanol solvent e.g. sodium ethoxide
  • the reaction mixture is then cooled, diluted with an excess of water, and acidified.
  • the product of formula IV can then be recoverd by filtration or by the standard procedure of solvent extraction.
  • the compound of formula III is reacted with from one to three equivalents, and preferably 1.2 to 1.5 equivalents, of the anhydride in the absence of solvent, at a temperature in the range from 80 to 130°C., and preferably about 100°C., for several hours (e.g., about 4 hours). If desired, however, an inert solvent such as toluene can be used.
  • the product of formula II can be recovered by removal of the excess anhydride and any solvent by evaporation. The crude product is usually pure enough for conversion into a compound of formula I.
  • the 2-oxindole compounds of formula III are prepared by known methods, or methods analogous to known methods. Consult: "Rodd's Chemistry of Carbon Compounds", Second Edition, S. Coffey editor, Volume IV Part A, Elsevier Scientific Publishing Company, 1973, pp. 448-450; Gassman et al., Journal of Organic Chemistry, 42,1340 (1977); Wright et al., Journal of the American Chemical Society, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 6093 (1968); United States Patients Nos.
  • the compounds of the formula I are acidic and they form base salts. All such base salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
  • Typical salts of the compounds of formula I which can be prepared are primary, secondary and tertiary amine salts, alkali metal salts and alkaline earth metal salts. Especially valuable are the ethanolamine, diethanolamine and triethanolamine salts.
  • Basic agents suitably employed in salt formation belong to both the organic and inorganic types, and they include organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides.
  • bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethylpiperidine, and N-methylmorpholine; hydroxides, such as sodium hydroxide; alkoxides, such as sodium ethoxide and potassium methoxide; hydrides, such as calcium hydride and sodium hydride; and carbonates, such as potassium carbonate and sodium carbonate.
  • primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benz
  • mice possess analgesic activity. This activity has been demonstrated in mice by showing blockade of the abdominal stretching induced by administration of 2-phenyl-1,4-benzoquinone (PBQ), using a method based on that of Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731, (1957), as adapted for high throughput (see further Milne and Twomey, Agents and Actions, 10, 31-37, [1980]). The mice used in these experiments were Carworth males, albino CF-1 strain, weighing 18-20 g. All mice were fasted overnight prior to drug administration and testing.
  • PBQ 2-phenyl-1,4-benzoquinone
  • the compounds of formula I were dissolved or suspended in a vehicle consisting of ethanol (5%), emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This vehicle also served as control. Doses were on a logarithmic scale (i.e., ... 0.32, 1.0, 3.2, 10, 32... mg/kg). The route of administration was oral, with concentrations varied to allow a constant dosage volume of 10 ml/kg of body weight. The aforesaid method of Milne and Twomey was used to determine efficacy and potency. Mice were treated with compounds orally, and one hour later received PBQ, 2 mg/kg, intraperitoneally.
  • % MPE degree of analgesic protection
  • the compounds of formula I also possess anti-inflammatory activity. This activity has been demonstrated in rats by a method based on the standard carrageenin-induced rat-foot edema test. (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, [1963]).
  • the analgesic activity of the compounds of formula I makes them useful for acute administration to mammals for the control of pain, e.g., post-operative pain and the pain of trauma. Additionally the compounds of formula I are useful for chronic administration to mammals for the alleviation of rheumatoid arthritis, and the pain associated with osteoarthritis and other musculoskeletal disorders.
  • a compound of the formula I or a pharmaceutically acceptable salt thereof When a compound of the formula I or a pharmaceutically acceptable salt thereof is to be used as either an analgesic agent or an anti-inflammatory agent, it can be administered to a mammalian subject either alone, or, preferably, in combination with pharmaceutically-acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice.
  • a compound can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.
  • the weight ratio of carrier to active ingredient will normally be in the range from 1:4 to 4:1, and preferably 1:2 to 2: 1. However, in any given case, the ratio chosen will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.
  • the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents are lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled to render the preparation isotonic.
  • the daily dosage will normally be determined by the prescribing physician. Moreover, the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the potency of the particular compound being administered. However, for acute administration to relieve pain, an effective analgesic response eliciting dose in most instances will be 0.1 to 1.0 g as needed (e.g., every four to six hours). For chronic administration to alleviate (treat) inflammation and pain, in most instances an effective dose will be from 0.1 to 1.5 g per day, and preferably 0.3 to 1.0 g per day, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • the solid was recovered by filtration and the gum was recovered by decantation. The gum was triturated under isopropanol-water giving further solid material, which was also recoverd by filtration. The two solids were combined and extracted with hot benzene, leaving a dark, gummy residue.
  • the benzene solution was cooled and evaporated in vacuo, and the residue was recrystallized from toluene to give 66 mg of the title compound, m.p. 136-137° C.
  • the mother liquors from the recrystallization were evaporated in vacuo and the latter residue was recrystallized from hexane to give a second crop, 90 mg, of the title compound, m.p. 135-136° C.
  • the second crop was submitted to elemental analvsis.
  • the ultraviolet spectrum of the product in methanol showed absorption maxima at 238, 260 and 290 millimicrons.
  • 3-(2-pyrrolylcarbonyl)-2-oxindole can be prepared by reaction of 2-oxindole with sodium ethoxide and ethyl pyrrole-2-carboxylate in ethanol.
  • the dried solid was then added portionwise, during 10 minutes, to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol.
  • the resultant solution was heated under reflux for 10 minutes and then it was concentrated in vacuo to a gummy solid.
  • the gummy solid was dissolved in 400 ml of water and the aqueous solution thus obtained was decolorized with activated carbon and then poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing ice chips. A tan solid precipitated and it was collected by filtration and washed thoroughly with water.
  • the solid was dried and then it was washed with diethyl ether. Finally it was recrystallized from ethanol to give 48.9 g of the title compound, m.p. 193-195°C (dec).
  • 5-methylisatin was converted into 5-methyl-2-oxindole by treatment with hydrazine hydrate followed sodium ethoxide in ethanol.
  • the product melted at 173-174°C.
  • 3,4-Dimethylaniline was converted into 3,4-dimethylisonitrosoacetanilide by reaction with chloral hydrate and hydroxylamine, using the method described in "Organic Syntheses", Collective Volume I, page 327.
  • the 3,4-dimethyl-isonitrosoacetanilide was cyclized with sulfuric acid, according to the method of Baker et al., Journal of Organic Chemistry, 17, 149 (1952), to give 4,5-dimethylisatin (m.p. 225-226°C) and 5,6-dimethylisatin (m.p. 217-218°C).
  • 4,5-Dimethylisatin was converted into 4,5-dimethyl-2-oxindole, m.p. 245.5-247.5°C, by treatment with hydrazine hydrate, followed by sodium ethoxide in ethanol, substantially according to the procedure of Preparation 6.
  • 5-Methoxy-2-oxindole was prepared from 4-methoxyaniline in a manner similar to the procedure of Preparation 10, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite.
  • the title product melted at 150.5-151.6°C.
  • 5-Bromo-2-oxindole can be prepared by bromination of 2-oxindole; see further Beckett et al., Tetrahedron, 24, 6093 (1968) and Sumpter et al., Journal of the American Chemical Society, 67,1656(1945).
  • 5-n-Butyl-2-oxindole can be prepared by reaction of 5-n-butylisatin with hydrazine hydrate followed by sodium methoxide in ethanol, according to the procedure of Preparation 6.
  • 5-n-Butylisatin can be prepared from 4-n-butylaniline by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, according to the procedure of Parts A and B of Preparation 8.
  • 5-Ethoxy-2-oxindole can be prepared by conversion of 3-hydroxy-6-nitro-toluene into 3-ethoxy-6-nitrotoluene by standard methods (potassium carbonate and ethyl iodide in acetone), followed by conversion of the 3-ethoxy-6-nitrotoluene into 5-ethoxy-2-oxindole by the method described by Beckett et al., Tetrahedron, 24, 6093 (1968), for the conversion of 3-methoxy-6-nitrotoluene into 5-methoxy-2- oxindole.
  • 5-n-Butoxy-2-oxindole can be prepared in like manner, but substituting n-butyl iodide for ethyl iodide.
  • 5,6-Dimethoxy-2-oxindole can be prepared by the method of Walker, Journal of the American Chemical Society, 77, 3844 (1955).
  • 7-Chloro-2-oxindole can be prepared by the method described in United States Patent No. 3,882,236.
  • 4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole can be prepared by the method described in United States Patent No. 4,006,161.
  • 5-n-Butylthio-2-oxindole can be prepared in like manner, but substituting 4-butylthioaniline for the 3-methylthioaniline.
  • 6-Fluoro-2-oxindole can be prepared according to Protiva et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 (1979) and United States Patent No. 4,160,032.
  • 6-Trifluoromethyl-2-oxindole can be prepared according to Simet, Journal of Organic Chemistry, 28, 3580 (1963).
  • 6-Methoxy-2-oxindole can be prepared according to Wieland et al., Chemische Berichte, 96, 253 (1963).
  • 5-Nitro-2-oxindole can be prepared by the method of Sumpter et al., Journal of the American Chemical Society, 67, 499 (1945).
  • 5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole can be prepared by reaction of 5-cyclopropylisatin and 5-cycloheptylisatin, respectively, with hydrazine hydrate followed by sodium methoxide in ethanol, according to the procedure of Preparation 6.
  • 5-Cyclopropylisatin and 5-cycloheptylisatin can be prepared from 4-cyclopropylaniline and 4-cycloheptylaniline, respectively, by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, according to Parts A and B of Preparation 8.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP85306479A 1984-09-19 1985-09-12 Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds Expired EP0175551B1 (en)

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Application Number Priority Date Filing Date Title
AT85306479T ATE42950T1 (de) 1984-09-19 1985-09-12 Schmerzstillende und entzuendungshemmende 1,3diacyl-2-oxindolverbindungen.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US65237284A 1984-09-19 1984-09-19
US652372 1984-09-19
US747194 1985-06-20
US06/747,194 US4690943A (en) 1984-09-19 1985-06-20 Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds

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EP0175551A1 EP0175551A1 (en) 1986-03-26
EP0175551B1 true EP0175551B1 (en) 1989-05-10

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US (1) US4690943A (enrdf_load_stackoverflow)
EP (1) EP0175551B1 (enrdf_load_stackoverflow)
AU (1) AU556948B2 (enrdf_load_stackoverflow)
CA (1) CA1256104A (enrdf_load_stackoverflow)
DE (1) DE3570078D1 (enrdf_load_stackoverflow)
DK (1) DK162443C (enrdf_load_stackoverflow)
GR (1) GR852244B (enrdf_load_stackoverflow)
IE (1) IE58140B1 (enrdf_load_stackoverflow)
IL (1) IL76405A (enrdf_load_stackoverflow)
PH (1) PH21580A (enrdf_load_stackoverflow)

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US7186745B2 (en) 2001-03-06 2007-03-06 Astrazeneca Ab Indolone derivatives having vascular damaging activity

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RU2544852C2 (ru) 2009-10-14 2015-03-20 Ксенон Фармасьютикалз Инк. Способы синтеза спиро-оксиндольных соединений
CN102946859B (zh) 2010-02-26 2016-03-02 泽农医药公司 用于局部给药的螺-羟吲哚化合物的药物组合物及其作为治疗剂的用途
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CN104744338A (zh) * 2015-03-31 2015-07-01 天津维智精细化工有限公司 一种6-氯羟吲哚的合成方法
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DE3570078D1 (en) 1989-06-15
US4690943A (en) 1987-09-01
IL76405A0 (en) 1986-01-31
IL76405A (en) 1990-03-19
IE58140B1 (en) 1993-07-14
GR852244B (enrdf_load_stackoverflow) 1986-01-17
DK162443B (da) 1991-10-28
DK422485D0 (da) 1985-09-18
EP0175551A1 (en) 1986-03-26
DK162443C (da) 1992-03-23
IE852297L (en) 1986-03-19
CA1256104A (en) 1989-06-20
PH21580A (en) 1987-12-11
AU556948B2 (en) 1986-11-27
AU4756185A (en) 1986-04-10
DK422485A (da) 1986-03-20

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